T. Michael Underhill, Professor

During the last few years, much has been learned about the mechanisms that regulate the formation of the skeletal tissues. Several transcription factors critical to the chondrogenic and osteogenic program have been identified, and the importance of various growth factors and cytokines in these processes is also being established. My laboratory has recently established an important role for the retinoid signaling pathway in chondrogenesis (Weston et al, 2000, J. Cell Biol.; Weston et al. 2002, J. Cell Biol.) and recent evidence from our laboratory also demonstrates an important function for this pathway in osteogenesis (Sampaio and Underhill, in preparation). To better understand the mechanisms underlying the commitment and differentiation of skeletal progenitors, my lab has employed a functional genomics approach. Traditionally, the major limitation of this approach involves efficiently defining the function of potentially hundreds of differentially-expressed candidate genes. To circumvent this problem, the Underhill lab has developed various high-content screens to facilitate the analysis of gene function in chondrogenesis and osteogenesis. In this manner, hundreds-thousands of genes can be screened for their ability to promote or inhibit these programs. This approach together with complementary strategies (ie. transcriptional profiling with arrays, automation with robotics, etc.), are currently being used to delineate the molecular regulatory networks that underlie the formation of chondrocytes and osteoblasts. Such information is expected to contribute substantially to our basic understanding of skeletal development and remodeling, but will also lead to the identification of novel targets which will serve as new therapeutic avenues for the manipulation of the skeletal cell phenotype.